Update on brown tumor of hyperparathyroidism

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BACKGROUND
On the right and left sides of the thyroid, the parathyroid glands are presented in the form of four nodules in total, two apical and two basal 1 .Topographic variations are commonthe parathyroid glands can be located near the larynx or even in the mediastinum, near the thymus 1 .Microscopically, they are made up of two main types of cells, clear and oxyphilic; the former secrete parathyroid hormone (PTH), and the latter have a still obscure function-all are arranged in a chordonal arrangement, interspersed with lobes of fatty tissue 1,2 .
Parathyroid hormone is a calcitonin antagonist that directly acts on renal tubule cells, inhibiting phosphate reabsorption and regulating phosphaturia 1 .In the bones, it acts by stimulating the action of osteoclasts which, by enzymatic action, reabsorb the matrix and solubilize calcium 1 .Therefore, PTH plays a key role in serum calcium homeostasis [1][2][3] .
Brown tumor of hyperparathyroidism has a female predominance 4,5,14 in a ratio of 3:18 and increases in frequency with aging (especially after the age of 50 years) and after menopause, which is related to hormonal effects 4,5 .It is very rare before puberty, and its incidence increases with age 2,10 .
Hyperparathyroidism (HP) is a pathology characterized by an increase in PTH secretion despite an increase in calcium in the extracellular fluid 10 .The hormone acts by absorbing the calcium present in the bones through the action of osteoclasts and preventing the reabsorption of phosphate in the glomerular filtrate, which causes phosphaturia and hypophosphatemia 10 .It occurs more frequently in the white breed and is rare in the yellow breed, with an overall incidence of about 20/100,000 6 .In the United States, BTH occurs in less than 2% of all HP patients and is especially associated with the most severe forms of the disease and parathyroid carcinoma.The occurrence of HP in young people should raise the suspicion of hereditary diseases such as multiple endocrine neoplasia (MEN) syndrome 2,5 .
Secondary hyperparathyroidism is a frequent result of chronic renal failure (CRF) 5,7,14,16 , particularly in dialysis patients, leading to renal osteodystrophy, a clinical condition that commonly causes BTH 5,7,16 (present in up to 50% of cases) 5 , with extensive bone marrow osteofibrosis and increased osteoclastic bone resorption 7 .The kidneys are unable to produce calcitriol, which promotes the entry of calcium into the bones.In calcitriol scarcity, PTH levels increase, promoting the removal of calcium from the skeleton.Several factors contribute to this, including bone strength to PTH, increased phosphorus retention, which causes malabsorption of calcium in the gut, and inhibition of 1,25(OH)2D production by increased phosphorus 4 .

Update on brown tumor
Persistent tertiary hyperparathyroidism is characterized by excessive secretion of PTH after long-standing SHP, in which the stimulated parathyroids are no longer in reactive mode but have taken on quasi-autonomous function-not unlike PHP, leading to hypercalcemia 12 .In theory, THP occurs due to the monoclonal expansion of parathyroid cells that have acquired an altered setpoint of their calcium-sensing receptor, causing PTH to continue to be secreted despite high serum calcium levels 12 .Other rare causes of THP include X-linked hypophosphatemic rickets, adult-onset hypophosphatemic rickets (autosomal dominant), and oncogenic osteomalacia 12 .
It is important to distinguish between primary parathyroid disorder, in which there is excessive and incomplete PTH secretion, as occurs in PHP, and physiological situations in which these glands respond to stimuli that lead to increased PTH secretion, as in SHP 12 .From a biochemical point of view, the main difference between primary and SHP is that in the former, there is an increase in calcium and a reduction in phosphate 16,17 , and in the latter, there is normocalcemia 12 and hyperphosphatemia 16 .Although both SHP and THP result from chronic stimulation of PTH secretion, serum calcium is always normal in the former, while it is always elevated in the latter.The distinction between PHP and THP is usually evident to the extent that a clearly definable disorder is present, such as long-standing malabsorptive syndrome or chronic kidney disease (CKD), often after kidney transplantation 2,12 .
Vitamin D deficiency may be associated with elevated PTH 12 .Drugs such as lithium and thiazide diuretics may be associated with an increase in PTH levels 12 .

DIAGNOSIS
The diagnosis of BTH is based on clinical manifestations, laboratory tests, imaging evaluation, and anatomopathological study 9,18 .However, as these can be non-specific, it is necessary to maintain a high index of suspicion 9,18 , especially in those patients who do not have a diagnosis of HP 2,18 .
Brown tumor of hyperparathyroidism is an advanced HP finding 10 .Its clinical findings depend on the lesion's size and location and are nonspecific-some patients are asymptomatic.Bone fragility can lead to fractures 1,7,12,17 which, in turn, lead to pain and disability 7,12,18 .Injuries that affect the spine may be associated with spinal cord compression.Facial deformities can cause difficulty breathing and food swallowing 7 .
Many studies confirm that the clinical manifestations of HP are worse when there is a deficiency of vitamin D, making its dosage an important part of the screening of suspected vitamin D 14 .
The anatomopathological examination is the gold standard modality for the definitive diagnosis 9,19 of BTH.

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Guedes A et al.
fractures may occur 7,9,14 (Figure 2).Excessive resorption of the terminal phalanges can lead to acroosteolysis 7,10 .Severe resorption in the sacroiliac joints can cause pelvic deformities that lead to inability to walk 7 .Thoracic vertebral fractures can lead to an increase in its anteroposterior diameter, leading the thorax to take on a "bell-bottom" shape 7 .Abnormal curvature and vertebral rotation can lead to thoracic deformities 7 .

HISTOPATHOLOGY
Brown tumor of hyperparathyroidism consists of vascularized osteofibrous tissue, devoid of matrix.Microscopically, there is increased resorption of bony trabeculae, forming a "tunneling" or "dissection" pattern.Osteoclastic resorption 4,5,11,18,19 leads to microfractures and microhemorrhages that progressively produce a small vacuum that becomes confluent with others, making BTH visible macroscopically 3,5,6,8,11,16,18 .Osteoclasts consume the trabecular bone that osteoblasts establish, and this front of reparative bone deposition, followed by further resorption, can expand beyond the usual shape, from bone to the periosteum, and cause bone pain.Involvement of the bones by BTH weakens them, resulting in pathological fractures 4 .

DIFFERENTIAL DIAGNOSIS
The imaging and histological features of BTH overlap with findings common to different diseases, making differential diagnosis difficult 9,11,14,18 .However, the clinical history of PHP or CRF with SHP usually establishes the diagnosis 4.6 .
It is critical to distinguish BTH from other clinical conditions to avoid unnecessary surgical procedures 18 .
The clinical picture "stones, bones, and groans" can be reproduced in malignant neoplasms such as paraneoplastic syndrome, due to the high levels of PTH-related peptides (PTHrP) that simulate the effect of PTH.In these cases, BTH can be mistaken for bone metastases 12 .
If hypercalcemia is present, the first impression is often of a malignant lesion 14 .
Bone scintigraphy, which has hot spots and/or generally high absorption in PHP, lacks specificity as it can also be seen in a variety of other conditions associated with increased bone metabolism, such as trauma, infections, primary or secondary malignant bone lesions, osteomalacia, Paget's disease, and other osteometabolic diseases 14 .
Positron emission tomography-computed tomography does not reliably distinguish malignant from benign skeletal lesions 14 .
Even histology cannot guarantee a correct diagnosis, due to the large number of lesions with multinucleated giant cells 19 .Among the numerous lesions that present these characteristics on anatomopathological examination 11,14,18,19 , the most challenging differential diagnosis occurs between the giant cell tumor and the BTH 9,11,18 .Other lesions, such as reparative cell granulomas, aneurysmal bone cysts, and some types of osteosarcoma, may present macroscopic and microscopic features similar to BTH 14.18 .

TREATMENT
Treatment of BTH begins with the management of HP, usually by parathyroidectomy, and should occur after the correction of underlying metabolic issues 9,11 .After parathyroidectomy, most bone disorders resulting from BTH will resolve 2,9,11 .
If surgery is not the best treatment option, medical treatment of hypercalcemia, vitamin D deficiency, and hyperphosphatemia may be performed.Serial evaluation of serum calcium, phosphate, PTH, and vitamin D determines the need for treatment 5 .
Regarding the orthopedic approach to the lesions, some studies point to the previous fixation of the fractures, while others indicate the fixation after parathyroidectomy 15 .Prior treatment of fractures is appropriate in cases where there are severe bone lesions associated with hypercalcemia-surgery should be postponed until the manifestations of hypercalcemia are corrected, avoiding intraoperative adverse events 15 .If parathyroidectomy is defined to be performed prior to fracture fixation, one should be aware of the possibility of "starving bone" syndrome, a condition characterized by rapid, deep, and prolonged hypocalcemia, accompanied by hypophosphatemia and hypomagnesemia.Until hypocalcemia resolves, definitive fixation of fractures should be delayed 2,15 .

PROGNOSIS
Bone changes constitute a late presentation of HP.Bone involvement in HP has shown a significant decrease in incidence in recent decades (from 80 to only 15%) 5 , constituting a very rare presentation of PHP, especially in developed countries, where serum calcium measurement is routinely performed 14,18 .This fact is attributed to the early detection 4,5,8,14,15 of asymptomatic cases through the monitoring of serum calcium and the treatment 4,14 of PH in the early stages of the disease.Proactive therapeutic management has made the manifestation of BTH relatively more common in renal osteodystrophy 14 , and 5% of PH cases develop this condition, which usually indicates prolonged or more severe disease 5 .
Bone lesions resulting from BTH are usually resolved through parathyroidectomy.Proper management of HP results in decreased osteoclastic activity and new bone deposition 2,5 .

Figure 2 .
Figure 2. (A, B) A 23-year-old male patient with primary hyperparathyroidism due to parathyroid adenoma, evolving with a pathological fracture through the subtrochanteric bone lesion.(A) Fixation of the fracture with proximal femur nailing.(B) Appearance of the lesion after parathyroidectomy, shortly after fracture fixation.

Figure 3 .Figure 1 .
Figure 3.A 23-year-old male patient with a brown tumor of hyperparathyroidism secondary to parathyroid adenoma.Scintigraphy showing hyperuptake of the left parathyroid glands.